The present invention relates to a method and composition for treating multiple sclerosis, demyelinating diseases and other diseases belonging to the general category of immunodeficiency diseases.
Multiple sclerosis, one of the demyelinating diseases of unknown etiology, has been known as one of the most intractable diseases known in the world with no effective therapy having yet been developed for it (c.f.G. Kuroiwa, "Intractable Diseases-Study and Prospect", S. Okinaka, Ed., Tokyo Univ. Press, 1979, pp. 7-27, 1979).
For allergic demyelinating diseases in humans, however, a useful experimental model was developed in 1947 by three research groups independently but having recourse to the same technique. Freund et al. (J. Freund et al., J. Immunol. 57, 179, 1947), Kabat et al. (E. A. Kabat et al., J. Exp. Med., 85, 117, 1947) and Morgan et al. (I. M. Morgan et al., J. Exp. Med., 85, 131, 1947) disclosed the successful development of experimental allergic encephalomyelitis (EAE) in animals by injecting a homogenized emulsion of the animal brain employing Freund's complete adjuvant technique, and the death of the animals within two or three weeks of the treatment. Since then, EAE has been utilized as an experimental model in studies of multiple sclerosis and other diseases influenced by cellular immunodeficiency. Indeed, it has served as a rare and useful system for in vivo-screening of curatives and treatments for demyelinating diseases and other immunodeficiency and autoimmune diseases.
Drugs for which EAE has been employed as a screening system include steroid anti-inflammatory agents, nonsteroid anti-inflammatory agents such as Flubiprofen, Cyclosporin A (cf. A. N. Davison and M. L. Cuzner, Ed. "The Suppression of Experimental Allergic Encephalomyelitis and Multiple Sclerosis" Academic Press, 1980), and E. N. 3638 (S. Levine and R. Sowinshi, J. Immunol. 120, 602, 1978; P. Y. Paterson and D. Drobish, Science, 165, 191, 1969), Cyclophosphamide (S. Levine and R. Sowinshi, J Immunol 120, 602 1978), Nitridazole (P. Y. Paterson et al., J. Immunol., 118. p. 2151, 1977 and C. A. Bernard et al., Int. Arch. Allergy Appl. Immunol., 53, p. 555, 1977) and amino acid copolymer (R Arnon and D. Teitelbaum, "The Suppression of Experimental Allergic Encephalomyelitis and Multiple Sclerosis", Academic Press, p. 105, 1980). The responses of EAE against these drugs in screening processes have probably been due to the immunosuppressive effects of the drugs. Of these drugs, however, those which presented any positive effects were of the steroid family.
In inflammatory or rheumatic diseases, some steroids also work remarkably well. However, undesirable secondary effects are almost always involved in their clinical application so that the drugs of this family are gradually being replaced by newly developed non-steroidal ones. For multiple sclerosis and other autoimmune diseases, the development of non-steroidal drugs that would act efficaciously but not be accompanied by adverse side effects in therapy is likewise desired.
As a result of recent researches, multiple sclerosis has come to be recognized as a disease caused by viral infection and/or the malfunction of thymus dependent lymphocytes (T-cell) in which the problem resides in a reduction in the number of "suppressor T-cells" (M. A. Bach, Lancet, December, p. 1221, 1980 and Reinherz et al., New Engl. J. Med., 303, p. 125, 1980). As for biosubstances involved in the control, differentiation and function of T-cells, some high molecular weight proteins such as thymosin have become known in recent studies.
In 1976, a nonapeptide having an amino acid sequence: p-Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn-OH (p-Glu representing pyroglutamic acid) was isolated from a volume of pig serum by J. F. Bach et al., and was named Facteur Thymique Serique (FTS) or Serum Thymic Factor (J. F. Bach et al., Nature, 266, p. 55, 1977 and Jean-Marie Pleau et al., J. Biol. Chem. 252, p. 8045, 1977). The present invention then is directed to new uses and pharmaceutical compositions containing FTS. FTS has been thought to have the ability to efficiently induce T-cell differentiation and some researchers seem to think that there may be low molecular weight peptides in mice, humans and other animals which might have actions similar to FTS. The present inventors have for some years been conducting research relative to the low molecular peptide: FTS for applications to the therapy of multiple sclerosis and other immunodeficiencies. The discovery of the in vivo effects of FTS in delaying the onset of neurological and clinical signs in EAE guinea pigs and monkeys, in alleviating the symptoms and greatly increasing survival time and in the cure-rate of treated animals led them to work out the present invention.
An EAE system utilizable in laboratory study can be obtained in almost any species of animals when they are immunized with an extract of the animal brain such as the myelin basic protein emulsified in the Freund's complete adjuvant formulation. The most frequently employed systems are those in guinea pigs, mice and monkeys In guinea pigs that are immunized in this way the clinical symptoms of EAE generally develop rather acutely. The animals cease to show notable body weight gain and, at about the tenth day after immunization, the animals begin to lose weight. At about the twelfth day, ataxia and paralysis develop in the hind part of the bodies and death comes to each one thereafter. The observed symptoms are similar in mice although death does not necessarily follow and many have a chance to recover when diet and other conditions are improved.
In guinea pigs, recent progress in research has made it possible to develop, besides the rather acute type of EAE which causes the animals to die within ten to sixteen days after immunization, a more chronic type of EAE which manifests a retarded onset of the symptoms and the occurrence of death. This chronic type of EAE was developed by modifying the immunization technique and adjusting animal conditions including the selection of their age. A guinea pig in which such a rather chronic type of EAE is induced shows symptoms which more closely resembled multiple sclerosis of humans.
At this time, however, only the conventional, rather acute type of EAE animal system is generally employed by medical and pharmaceutical specialists for screening new drugs to be employed in the treatment of EAE. Even new curatives for treating EAE, including steroids, which have been developed under such circumstances continue to give only a limited contribution to the prolongation of the lives of animals suffering from demyelinating diseases or other diseases of this category.